6-(cyanophenyl)-4,5-dihydro-3(2h)-pyridazinones

ABSTRACT

THIS DISCLOSURE DESCRIBES COMPOUNDS OF THE CLASS OF 6-(O, M-, OR P-CYANOPHENYL)-4,5-DIHYDRO-3-(2H) - PYRIDAZINONES USEFUL AS HYPOTENSIVE AGENTS.

US. Cl. 260-250 A 9 Claims ABSTRACT OF THE DISCLOSURE This disclosuredescribes compounds of the class of 6-(0, m-, orp-cyanophenyl)-4,5-dihydro-3(2H) pyridazinones useful as hypotensiveagents.

CROSS REFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of our copending application Ser. No. 79,670, filedOct. 9, 1970, now abandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to new organiccompounds and,

more particularly, is concerned with novel 6-(0-, m-, orp-cyanophenyl)-4,5-dihydro 3(2H) pyridazinones and with methods ofpreparing these compounds. The novel compounds of the present inventionmay be represented by the following general formula:

wherein R is hydrogen or lower alkyl, R is hydrogen or methyl, and R isortho-cyano, meta-cyano or para-cyano. Suitable lower alkyl groupscontemplated by the present invention are those having up to four carbonatoms such as, for example, methyl, ethyl, n-propyl, isopropyl,isobutyl, sec-butyl, etc.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the presentinvention are generally obtainable as white or pale yellow to orangecrystalline materials having characteristic melting points andabsorption spectra and which may be purified by recrystallization fromcommon organic solvents such as methanol, ethanol, anddimethylformamide. They are appreciably soluble in many organic solventssuch as ethyl acetate, chloroform, dimethylsulfoxide, and the like'butare relatively insoluble in water.

The novel compounds of the present invention wherein R is hydrogen ormethyl may be readily prepared by the interaction of an appropriatelysubstituted 3-benzoylpropionic acid with hydrazine or methylhydrazine inaccordance with the following reaction scheme o @Ji-oH-omoom R3 R2 H(orCH,

wherein R and R are as hereinabove defined. This reaction is preferablycarried out in a solvent such as a United States Patent O lower alkanol,dioxane, tetrahydrofuran, and the like, at steam bath temperature for aperiod of time of a few hours. The hydrazine is preferably employed inthe form of the hydrate. The final products are isolated from thereaction mixtures and purified by conventional means well known to thoseskilled in the art.

The novel compounds of the present invention wherein R is lower alkylmay be readily prepared by alkylating 6-(0-, m-, orp-cyanophenyl)-4,5-dihydro-3(2H)-pyridazinone or 6-(0-, m-, orp-cyanophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone with theappropriate lower alkyl halide. Suitable lower alkyl halides which may-be thus employed are, for example, methyl iodide, ethyl iodide,n-propyl bromide, iso-propyl iodide, n-butyl chloride, is0- butylbromide, sec-butyl iodide, and the like. The reac tion is best carriedout in the presence of powdered potassium hydroxide in an inert solventsuch as acetone, dioxane, tetrahydrofuran, etc., at the refluxtemperature for a few hours. The final products are isolated from thereaction mixtures and purified by conventional means well known to thoseskilled in the art.

Alternatively, the cyano compounds may be prepared by diazotization ofan appropriately substituted 6-(0-, m-, or p-aminophenyl 4,5 dihydro3(2H) pyridazinone (British Pats. No. 1,164,139 and No. 1,168,291) andreplacement of the diazonium group with a cyano group. The diazotizationis preferably carried out by addiing sodium nitrite to a solution of theamine in dilute hydrochloric acid at a temperature of 0-5 C. An excessof mineral acid is used over and above the amount needed to form thesalt of the amine and to decompose the sodium nitrile. The resultingsolution of diazonium salt is neutralized with a base, such as sodiumbicarbonate, and added to a cold (10-l5 C.) aqueous solution of cuprouscyanide and potassium cyanide. After the addition, the resultingsolution is stirred at room temperature for 10-20 hours during whichtime the desired cyano compound precipitates from the solution.

Typical compounds of the present invention which may be prepared by theabove methods are, for example,

6- (o-cyanophenyl-4,5-dihydro-3 2H -pyridazinone,

6- (o-cyanophenyl) -5-methyl-4,5-dihydro-3 2H) pyridazinone,

6-(0-cyanophenyl) -2-methyl-4,5-dihydro-3 (2H) pyridazinone,

6- (m-cyanophenyl) -2-methyl-4,5-dihydro-3 (2H) pyridazinone,

6- (p-cyanophenyl) -2-methyl-4,5-dihydro-3 (2H) pyridazinone,

6- (o-cyanophenyl) -2,5-dimethyl-4,5-dihydro 3 (2H pyridazinone,

-6-(o-eyanophenyl)-2-ethyl-4,5'-dihydro-3 (2H)- 6 (o-cyanophenyl -2-(rt-propyl --methyl-4,5-dihydro- 3 (2H) -pyridazinone,

6- (m-cyanophenyl) -2-isopropyl-5-methyl-4,5-dihydro- 3 (2H-pyridazinone,

6-(p-cyanophenyl) 2- (n-butyl- -5-methyl-4,5-dihydro- 3 2H)-pyridazinone,

6- (o-cyanophenyl) -2-isobutyl-5-methyl-4,S-dihydro- 3 (2H)-pyridazinone,

G-(m-cyanophenyl) -2- (sec-butyl) -5-methyl-4,5-dihydro- 3 (2H)-pyridazinone,

and the like.

The novel compounds of the present invention have long lastinghypotensive activity which was demonstrated in the following testprocedure. Conscious male albino Sherman strain rats averagingapproximately 250 grams in weight were fastened to rat boards in asupine position by means of canvas vests and limb ties. The femoralareas were anesthetized (subcutaneous infiltration of lidocaine), andthe left or right common iliac arteries were exposed and clamped offproximally by an artery clamp and distally with thread. Incisions weremade near the tie and short nylon catheters were inserted and tied inplace. The other end of the catheters were fitted with 24 gauge hublessneedles attached to thickwalled polyethylene tubes. The test compoundswere administered to the animals orall by gavage (stomach tube). Thetest compounds were ordinarily suspended or dissolved in 2 percentaqueous starch solution, one milliliter of which gave, per 100 grams ofbody weight, the desired dose. Mean arterial blood pressure was measured4 and 24 hours after administration of the compounds. Comparisons werethen made to the mean control pressure of 121:7 mm. of mercury which isthe average and standard deviation of a number of controls recorded overmonths of testing. Blood pressure measurements were made with fourStatham P23 Db strain guages (Statham Instruments, Inc. Los Angeles,California), attached to a Sanborn Polyviso Recorder equipped with fourstrain gauge preamplifiers with averaging circuits for measuring meanarterial pressure. Table I summarizes the activity of typical compoundsof the present invention and compares them with two previously disclosedcompounds. It is obvious from an examination of Table I that thecompounds of this invention possess hypotensive activity which isconsiderably longer lasting than that of the previously disclosedcompounds.

All compounds dosed at 100 mgJkg. of body weight. "Disclosed in U.S.Pat. No. 3,475,431.

The novel compounds of the present invention may be administered eitherorally or parenterally. The amount of a single dose or of a daily doseto be given will vary but should be such as to give a proportionatedosage of from about one mg. to about 15 mg. per kilogram of body weightper day. Thus, such dosage units are employed that a total of from about50 mg. to about 1.0 g. for a subject of about 70 kg. body weight areadministered in a 24 hours period. The dosage regimen may be adjusted toprovide the optimum therapeutic response, for example, several doses of25-250 mg. may be administered daily or the dose may be proportionatelyreduced as indicated by the exigencies of the therapeutic situation.

The compounds may be orally administered, for example, with an inertdiluent or with an assimilable edible carrier, or they may be enclosedin hard or soft shell gelatin capsules, or they may be compressed intotablets, or they may be incorporated directl with the food of the diet.For oral therapeutic administration, the novel compounds of thisinvention may be incorporated with excipients and used in the form oftablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage in the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 5% to about 75% or more of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions orpreparations in such that a suitable dosage will be obtained. Preferredcompositions or preparations are prepared so that an oral dosage unitform contains between about 25 and 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose, or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar, or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

Compositions having the desired clarity, stability, and adaptability forparenteral use are obtained b dissolving from 0.10% to 10.0% by weightof a 6-(o-, m-, or pcyanophenyl) 4,5 dihydro 3(2H) pyridazinone is avehicle consisting of a mixture of non-volatile, normally liquidpolyethylene glycols which are soluble in both water and organic liquidsand which have molecular weights of from about 200 to about 1500. Suchmixtures of polyethylene glycols are commercially available and areusually obtained by condensing glycol with ethylene oxide. Although theamount of 6-(0-, m-, or p-cyanophenyl)-4,5- dihydro 3(2H) pyridazinonedissolved in the above vehicle may vary from 0.10% to 10.0% by weight,it is preferred that the amount employed be from about 3.0% to about9.0% by weight. Although various mixtures of the aforementionednonvolatile polyethylene glycols may be employed, it is preferred to usea mixture of nonvolatile polyethylene glycols having an averagemolecular weight of about 400. Such a mixture is usually referred to aspolyethylene glycol 400. A preferred embodiment comprises a clearsolution of from about 3.0% to about 9.0% by weight of the 6-, o-, m-,or p-, -cyanophenyl)-4,5- dihydro 3(2H) pyridazinone dissolved in anaqueous solution of polyethylene glycol 400. In addition to the 6-(o-,m-, or p-cyanophenyl) 4,5 dihydro 3(2H)- pyridazinone, the parenteralsolutions ma also contain various preservatives wihch may be used toprevent bacterial and fungal contamination or chemical degradation.

EXAMPLE 1 Preparation of 6-(p-cyanophenyl)-4,5-dihydro-3 (2H)-pyridazinone A solution of 3.8 g. of 6-(p-aminophenyl)-4,5-dihydro- 3(2H)-pyridazinone in 150 ml. of water containing 15 ml. of concentratedhydrochloric acid is cooled to 5 C. and a cold solution of sodiumnitrite (1.4 g. in 10 ml. of water) is added in several portions. Thissolution is neutralized with sodium carbonate and added to a stirred,cold solution of 2.24 g. of cuprous cyanide and 4.0 g. of potassiumcyanide in 100 ml. of water. The mixture is stirred at room temperatureovernight, then the orange crystalline precipitate is collected; M.P.245 255 C. dec.

EXAMPLE 2 Preparation of 6-(m-cyanophenyl)-4,5-dihydro-3(2H)-pyridazinone A solution of 3.8 g. of6-(m-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 9 ml. ofconcentrated hydrochloric acid plus 100 ml. of water is cooled to -3 C.A cold solution of 1.4 g. of sodium nitrite in 10 ml. of water is added,and the pH is carefully adjusted to 5.5. This solution is added slowlyto a vigorously stirred, cold solution of 2.23 g. of cuprous cyanide and4.0 g. of potassium cyanide in 20 ml. of water. The reaction mixture isstirred at room temperature for 4 hours and then at 50 C. for 30minutes. The orange crystalline solid is filtered 01f and recrystallizedfrom ethanol; m.p. 187.5 l88.5 C.

EXAMPLE 3 Preparation of 6- (p-morpholinophenyl -4,5-dihydro- 3 2H)-pyridazinone 3-(p-Morpholinopbenzoyl)propionic acid (1.3 g.), 0.2 ml.of hydrazine and ml. of ethanol are refluxed for 3 hours. The solutionis cooled, and the crystals which formed are recrystallized fromethanol-water; m.p. 220- 221.5 C.

EXAMPLE 4 Preparation of 3-(p-acetamidobenzoyl)crotonic acid Groundacetanilide (135 g.) is added to a cold mechanically stirred, suspensionof 490 g. of aluminum chloride in 650 ml. of carbon disulfide. Thevigorous exotherm which occurs yields a thick, black sludge, and is 112g. (90 ml.) of citraconic anhydride is added, the mixture becomes moremobile. The mixture is refluxed with stirring until the stirrer stopsand then is allowed to stand at room temperature for five .days. Afterthe carbon disulfide is decanted, the complex is decomposed using iceand 37% hydrochloric acid. The aqueous layer and solid are extractedwith benzene and then into aqueous bicarbonate. The bicarbonate solutionis treated with activated carbon and acidified to pH 2 to precipitate abrown gum (ca. 98 g.). The gum is stirred with ethyl acetate. The ethylacetate layer is dried over magnesium sulfate and evaporated to an oilwhich is crystallized from acetone-water to give in three crops 51 g. ofoff-white crystals, m.p. l30- 136 C.

EXAMPLE 5 Preparation of B-(p-acetamidobenzoyl)butyric acid To asolution of 5.0 g. of 3-.(p-acetamidobenzoyl)crotonic acid in 45 ml.water and 3.0 ml. glacial acetic acid is added 3.0 g. zinc dust and themixture is heated on a steam bath for 30 minutes. Solid material isfiltered off and concentrated hydrochloric acid is added to the filtrateuntil the product oils out. The oil is separated, washed with water, andcrystallizsed from ethanol-Water to give 4.6 g. (92%) of white crystals,m.p. 94.5103.0 C. Recrystallization from a small volume of ethanol gives2.6 g. of white crystals, m.p. 147-149 C.

EXAMPLE 6 Preparation of 4'-(1,4,5,6-tetrahydro-4-methyl-6-oxo- 43-pyridazinyl acetanilide A solution of 3.9 g. of3-(p-acetamidobenzoyl)butyric acid and 1.7 ml. of 99% hydrazine hydratein 25 ml. of ethanol is heated at reflux temperature for 2 hours. Themixture is cooled in an ice-bath and filtered to give 2.57 g. of whitecrystals, m.p. 238239 C.

EXAMPLE 7 Preparation of 6- (p-aminophenyl -4,5-dihydro-5-methyl- 3 (2H)-pyridazinone A mixture of 2.5 g. of 4'-(l,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)acetanilide, 25 ml. of 10N sodium hydroxide solutionand 25 ml. of methanol is heated at reflux temperature for 2.5 hours.The methanol is removed by evaporation and the residual solution iscooled, diluted with water, and stored at 4 C. for 16 hours. Filtrationgives 1.3 g. of white crystals, m.p. 195 197 C.

EXAMPLE 8 Preparation of p-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl benzonitrile Using the procedure of Example 1, treatment of6.65 g. of 6- p-aminophenyl -4,5 -dihydro-5 -methyl-3- 2H) -pyridazinonein ml. of water containing 13.3 ml. of 37% hydrochloric acid solutionwith an aqueous solution of 2.38 g. of sodium nitrite gives a solutionwhich is neutralized with sodium carbonate and stirred with 3.79 g. ofcuprous cyanide and 6.65 g. of potassium cyanide. Filtration furnishes6.47 g. of product as yellow crystals, m.p. 194-196 C.

EXAMPLE 9 Preparation of 4,5-dihydro-5-methyl-6-(m-nitrophenyl)- 3(2H)-pyridazinone 3-Benzoylbutyric acid (2.5 g.) [Lutz et. al., J.A.C.S.75, 5039 (1953)] is dissolved in 20 ml. of conc. nitric acid, cooled and20 ml. of conc. sulfuric acid is added over 30 minutes with stirring.The mixture is then stirred at room temperature for 1.5 hours and thenpoured onto ice. The resulting gum is extracted with chloroform which iswashed with saturated salt solution then dried (MgSO Evaporation of thechloroform gives 3-(m-nitrobenzoyl) butyric acid.

The above acid is refluxed for 1.0 hour in 20 ml. of ethanol containing1.0 ml. of hydrazine hydrate, treated with Norit, and filtered. Thefiltrate deposited 0.55 g. of crystals of the product: m.p. 189 -192 C.For analytical purposes this product is recrystallized from ethanol toafford light yellow crystals: m.p. 19l-l94 C.

EXAMPLE 10 Preparation of 6-(m-anilino)-5,6-dihydro-5-methyl- 3 (2H)-pyridazinone A mixture of 4,5-dihydro-5-methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone (0.5 g.), 0.25 g. of 10% palladiumon-carbon, 20 ml.of ethanol, and 10 ml. of cyclohexene is refluxed for 18 hours,filtered, and evaporated to give an oil which crystallizes.Recrystallization from ethyl ace- 7 tate-hexane and then from ethanolalfords 0.2 g. (46%) of the product: m.p. 143 -145 C.

EXAMPLE 11 Preparation of m- 1,4,5 ,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile Using the procedure of Example 1, 6.65 g. of6-(manilino)-5,6-dihydromethyl-3 (2H)-pyridazinone gives 6.56 g. of theproduct as pale yellow crystals, m.p. 189 191 C.

EXAMPLE 12 Preparation of p-(l,4,5,6-tetrahydro-1,4-dimethyl-6-oxo-3-pyridazinyl) benzonitrile A mixture of 330 mg. ofp-(1,4,5,6-tetrahydro-4-methyl- 6-oxo-3-pyridazinyl)benzonitrile and 430mg. of powdered potassium hydroxide in 10 ml. of acetone is treated with1 ml. of methyl iodide. The mixture is stirred at reflux temperature for30 minutes, after which the volatile material is removed under reducedpressure. The residue is triturated with water to give a solid that iscollected by filtration and then recrystallized from methylenechloridepetroleum ether (b.p. 30-60 C.) to give 260 mg. of yellowcrystals, m.p. 170-172 C.

EXAMPLE 13 Preparation of m-(1,4,5,6-tetrahydro-1,4-dimethyl-6- oxo-3-pyridazinyl) benzonitrile Using the procedure of Example 12, 1.00 g. ofm-(l,4, 5,6 tetrahydro 4 methyl-6-oxo-3-pyridazinyl)benzonitrile, 1.29g. of powdered potassium hydroxide and 3 ml. of methyl iodide in 30 ml.of acetone give an oil that crystallizes on trituration with petroleumether containing a little ether. Recrystallization of the solid frometherpetroleum ether (b.p. 30-60 C.) gives 450 mg. of yellow crystals,m.p. 80-81 C.

EXAMPLE 14 Preparation of p-(l-ethyl-1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl benzonitrile Preparation of3-(p-cyanobenzoyl)propionic acid To a cold, stirred solution of 25.0 g.of p-aminobenzoylpropionic acid {prepared by alkaline hydrolysis ofp-acetamidobenzoylpropionic acid [J. P. English et al., J. Amer. Chem.Soc. 67, 2263 (1945)]} in 600 ml. of water containing 100 ml. ofconcentrated hydrochloric acid is added a cold solution of sodiumnitrite (9.1 g.) in 60 ml. of water over 15 minutes. The solution iscarefully neutralized with sodium carbonate and then added, in severalportions, to a cold, stirred solution of cuprous cyanide (14.0 g.) andpotassium cyanide (20.0 g.) in 400 ml. of water which is covered withml. of toluene. The mixture is stirred in the cold for 0.5 hour and thenat room temperature overnight. Filtration removes a small amount ofyellow solid and the filtrate is acidified with 50 ml. of concentratedhydrochloric acid. The resulting dark brown solid is collected andextracted with a boiling solution of 800 ml. of chloroformzbenzene 1:1).The extract deposits orange crystals on cooling; 11.2 g. m.p. 157-161 C.For analytical purposes a sample is recrystallized from ethyl acetate.The melting point is raised to 161-163.5 C.

EXAMPLE 16 Preparation of 6-(p-cyanophenyl)-4,5-dihydro-2- methyl-32H)-pyridazinone A solution of 2.00 g. of 3-(p-cyanobenzoyl)propionicacid and 2.00 ml. of methylhydrazine in 50 ml. of ethanol containing sixdrops of glacial acetic acid is heated at reflux temperature for 4hours. The solution is concentrated until solid begins to separate. Themixture is cooled and filtered to provide the product as white crystals,m.p. 138-140 C.

What is claimed is:

1. A compound of the formula:

1 N-N Q wherein R is selected from the group consisting of hydrogen andalkyl having up to four carbon atoms, R is selected from the groupconsisting of hydrogen and methyl, and R is selected from the groupconsisting of metacyano and para-cyano.

2. The compound according to Claim 1 wherein R and R are hydrogen and Ris para-cyano.

3. The compound according to Claim 1 wherein R and R are hydrogen and Ris meta-cyano.

4. The compound according to Claim 1 wherein R is methyl, R is hydrogenand R is para-cyano.

5. The compound according to Claim 1 wherein R and R are methyl and R ispara-cyano.

6. The compound according to Claim 1 wherein R is hydrogen, R is methyland R is para-cyano.

7. The compound according to Claim 1 wherein R is hydrogen, R is methyland R is meta-cyano.

8. The compound according to Claim 1 wherein R and R are methyl and R ismeta-cyano.

9. The compound according to Claim 1 wherein R is ethyl, R is methyl andR is para-cyano.

References Cited Schier and Marxer; Antihypertensive Agents, 1962- 1968in Fortschr. Arzneimittelforsch. 13, 117 (1969), Augstein, et al.: J.Med. Chem. 8, 356-359 (1965).

Short and Darby, J. Med. Chem. 10, 833-35 (1967).

Gadekar, et al.; J. Med. Chem. 1], 811-813 (1968).

DONALD G. DAUS, Primary Examiner R. D. McCLOUD, Assistant Examiner US.Cl. X.R. 260465 D; 424250

